The broad long-term goal of this application is to identify novel ligands for cell surface receptors, and to characterize functions in vertebrate development, particularly development of neural connections. Aim 1 focuses on identification of novel ligands. The first part of aim 1 deals with receptor-like protein tyrosine phosphatases of the mammalian LAR family. Previous genetic studies show functions for these molecules in neural development, but their actions and putative ligands are still not well understood. In preliminary studies, a novel family of three ligands has been molecularly identified, and will be characterized further. The second part of aim 1 deals with the Amyloid Precursor Protein (APP), which is cleaved to form the beta-amyloid peptide implicated in Alzheimer's disease. Despite its pathological relevance, the natural function of APP is not well understood. It has long been suggested that APP may function as a ligand or receptor, and in preliminary studies we have shown a novel-binding pattern to developing axons. Further studies are proposed to identify and characterize the ligand(s) responsible for this binding. Aim 2 proposes continued studies on developmental functions of the ephrins, a family of ligands identified during earlier cycles of the project. The focus is on experiments to elucidate novel principles of ephrin function, such as roles in coordinating cortical cell migration, and roles at the synapse. Aim 3 is to develop new small-molecule approaches to study axon outgrowth and guidance. A "chemical genetic" screen is proposed, to identify chemical compounds that modulate the inhibitory effect of ephrins, as well as other molecular cues that inhibit axon growth during development and regeneration. While this work focuses on basic biology, studies to identify, characterize, and modulate novel cell-cell signaling molecules may ultimately lead to therapeutic agents for maintenance, repair or regeneration of neural connections. Also, our studies on APP ligands may lead to new strategies to regulate proteolytic processing, with potential implications for Alzheimer's disease. Aim 3, involving a screen for chemical compounds that can promote axon growth and regeneration, focuses on basic cell biology but could produce compounds or lead-compounds for further therapeutic development for treatment of nerve injury.